The transmissible spongiform encephalopathies (TSEs or prion diseases)are fatal untreatable neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). TSE pathogenesis involves the accumulation of an abnormal misfolded protein, called PrPres, in infected hosts. In FY 2013: 1) We have collaborated with extramural investigators to identify a designed Trpzip-3 β-hairpin that inhibits amyloid formation in two different amyloid systems. 2) We have continued to search for new anti-prion compounds from libraries of novel compounds that have been synthesized in Brazil by our collaborators. A number of new compounds have been identified that block PrP-res formation and have other attractive characteristics, but further testing of these compounds will be required to better establish their therapeutic potential.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$131,208
Indirect Cost
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Kellock, Jackson; Hopping, Gene; Caughey, Byron et al. (2016) Peptides Composed of Alternating L- and D-Amino Acids Inhibit Amyloidogenesis in Three Distinct Amyloid Systems Independent of Sequence. J Mol Biol 428:2317-28
Vieira, Tuane C R G; Cordeiro, Yraima; Caughey, Byron et al. (2014) Heparin binding confers prion stability and impairs its aggregation. FASEB J 28:2667-76
Hopping, Gene; Kellock, Jackson; Barnwal, Ravi Pratap et al. (2014) Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers. Elife 3:e01681
Ferreira, Natalia C; Marques, Icaro A; Conceicao, Wesley A et al. (2014) Anti-prion activity of a panel of aromatic chemical compounds: in vitro and in silico approaches. PLoS One 9:e84531
Hopping, Gene; Kellock, Jackson; Caughey, Byron et al. (2013) Designed Trpzip-3 β-Hairpin Inhibits Amyloid Formation in Two Different Amyloid Systems. ACS Med Chem Lett 4:824-8
Wolfe, Lisa L; Kocisko, David A; Caughey, Byron et al. (2012) Assessment of prospective preventive therapies for chronic wasting disease in mule deer. J Wildl Dis 48:530-3
Taubner, Lara M; Bienkiewicz, Ewa A; Copié, Valérie et al. (2010) Structure of the flexible amino-terminal domain of prion protein bound to a sulfated glycan. J Mol Biol 395:475-90
Sim, Valerie L; Caughey, Byron (2009) Recent advances in prion chemotherapeutics. Infect Disord Drug Targets 9:81-91